Research consistently shows that stress negatively affects both mental and physical health. Yet models of stress have thus far not investigated the individual differences in neurocognitive processes that translate perceptions of threat into psychological, physiological, neuroendocrine, and immunological stress responses. That is, no studies to date have examined the complete relationship between the brain's response to threat and the ensuing biological and psychological stress responses, and how these pathways are moderated by key individual differences related to stress reactivity and coping. We hypothesize that the anterior cingulated cortex (ACC) and the amygdala are critically involved in these pathways and that the prefrontal cortex (PFC) regulates the reactivity of this pathway. We will test these relations in the proposed project. In a parent project (MH506880), participants complete individual difference measures of neuroticism, self-esteem, and optimism and participate in a laboratory stress challenge (the TSST), during which autonomic responses, cortisol, and pro-inflammatory cytokines are assessed at baseline, following the stress challenge, and following a recovery period. The current proposal seeks to add a neuroimaging component to this project. We will select a sample of 30 participants from the parent project to complete tasks previously demonstrated to evoke ACC (Cyberball and Go-NoGo tasks) and amygdala (Threat Perception task) activity; as well as PFC activity involved in negative emotion regulation (Cyberball task). We will use these measures to assess whether the magnitude of the ACC, amygdala, and PFC responses is related to individual differences in neuroticism, optimism, and self-esteem and to autonomic, neuroendocrine, and immunologic stress reactivity. We test the predictions that neuroticism will be negatively associated with PFC activity and positively associated with ACC, amygdala, and stress reactivity whereas self-esteem and optimism will show the opposite pattern, correlating positively with PFC activity and negatively with ACC, amygdala, and stress reactivity. Evidence in support of these novel hypotheses will greatly enhance understanding of stress processes and will provide the first investigation in humans of the role of neural mechanisms in mediating the pathway from environmental threat to biological stress reactivity. As such, the proposed work integrates research from health psychology, psychoneuroimmunology, and social neuroscience. Supportive evidence will flesh out the neural mechanisms through which individual differences affect biological responses to stress and elucidate the risk factors for stress- related mental and physical health problems.